Abstract Ferroptosis is a recently recognized form of regulated cell death driven by lipid peroxidation. It is an emerging field in cancer biology, and the detailed molecular regulators of ferroptosis are largely unknown. We recently demonstrated that upregulation of metallothionein (MT)-1G expression contributes to ferroptosis resistance in human hepatocellular carcinoma cells, whereas inhibition of MT-1G expression enhances ferroptosis sensitivity in vitro and in vivo (Hepatology. 2016 63(1):173-184.; Hepatology. 2016 64(2):488-500.). These exciting findings raise several important questions regarding the previously unidentified role of MT-1G in the regulation of ferroptotic cancer cell death. Our central hypothesis is that expression and release of MT-1G limits ferroptotic cancer cell death. To test this hypothesis, we will exploit molecular, cellular, and animal models to pursue the following aims. Aim 1: Define the mechanism responsible for transcriptional regulation of MT-1G expression in ferroptosis. Aim 2: Define the mechanism responsible for phosphorylation modification of MT-1G function in ferroptosis. Aim 3: Define the mechanism responsible for extracellular activity of MT-1G in ferroptosis. The completion of these exciting studies will improve our understanding of the cancer molecular pathobiology of ferroptosis and guide future development of novel MT-1G-based anticancer therapeutic strategies.